CA2446326A1 - 4(phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders - Google Patents

4(phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders Download PDF

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CA2446326A1
CA2446326A1 CA002446326A CA2446326A CA2446326A1 CA 2446326 A1 CA2446326 A1 CA 2446326A1 CA 002446326 A CA002446326 A CA 002446326A CA 2446326 A CA2446326 A CA 2446326A CA 2446326 A1 CA2446326 A1 CA 2446326A1
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compound
formula
methyl
phenyl
fluoro
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CA2446326C (en
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William Brown
Christopher Walpole
Niklas Plobeck
Thomas Hudzik
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AstraZeneca AB
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Priority claimed from SE0103820A external-priority patent/SE0103820D0/en
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

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  • Addiction (AREA)
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  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
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  • Psychology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Transplantation (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Compounds of general formula I R1 is selected from any one of phenyl, pyridinyl, thienyl, furanyl, imidazolyl, pyrrolyl, triazolyl, thiazolyl, and pyridine N-oxide; R2 is independently selected from ethyl and isopropyl; R3 is independently selected from hydrogen and fluoro; R4 is independently selecte d from -OH, -NH2 and -NHSO2R5; and R5 is independently selected from hydrogen, - CF3 and C1-C6 alkyl, or salts thereof or separate enantiomers and salts thereof; where each R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iod o. The substitutions on the heteroaromatic ring may take place in any position on said ring systems; are disclosed and claimed in the present application, as well as separate enantiomers of the compounds and salts and pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain, anxiety and functional gastrointestina l disorders.

Claims (15)

1. A compound of the formula I
wherein R1 is selected from any one of (ii) phenyl;
(iii) pyridinyl (iii) thienyl (iv) furanyl (v) imidazolyl (vi) triazolyl (vii) pyrrolyl (viii) thiazolyl (ix) pyridyl-N-oxide wherein each R1 heteroaromatic ring may optionally and independently be further substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6 alkyl, halogenated C1-C6 alkyl, NO2, CF3, C1-C6 alkoxy, chloro, fluoro, bromo, and iodo;

R2 is independently selected from ethyl and isopropyl;
R3 is independently selected from hydrogen and fluoro;
R4 is independently selected from -OH, -NH2 and -NHSO2R5; and R5 is independently selected from hydrogen, -CF3 and C1-C6 alkyl, or salts thereof or separate enantiomers and salts thereof, provided that when R2 is ethyl and R3 is hydrogen then R4 cannot be -OH.
2. A compound according to claim 1, wherein R1 is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R2 is ethyl or isopropyl; R3 is hydrogen or fluoro; R4 is -NH2 or -NHSO2R5; and R5 is C1-C6 alkyl.
3. A compound according to claim 1, wherein R1 is phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R2 is ethyl or isopropyl; R3 is hydrogen; R4 is -NHSO2R5; and R5 is C1-C6 alkyl.
4. A compound according to claim 1, wherein the heteroaromatic ring(s) are substituted by CF3, methyl, iodo, bromo, fluoro or chloro.
5. A compound according to claim 1, wherein the heteroaromatic ring(s) are substituted by methyl.
6. A compound according to claim 1, selected from any one of 4-[1-(4-Benzyl-piperazin-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl]-N,N
diisopropyl-benzamide;
4-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;
4-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide;
4-[1-(3-Amino-phenyl)-1-(4-benzyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;

4-[1-(3-Amino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-N,N-diisopropyl-benzamide;
4-{1-(3-Amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-yl]-methyl}-N,N-diisopropyl-benzamide;
N,N-Diisopropyl-4-[1-(3-methanesulfonylamino-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-methyl]-benzamide;
4-([4-(3-furylmethyl)-1-piperazimyl]{3-[(methylsulfonyl)amino]phenyl}-N,N-diisopropyl-benzamide;
4-{(3-aminophenyl)[4-(3-thienylmethyl)-1-piperazinyl]methyl}-N,N-diethylbenzamide;
4-[(3-aminophenyl)(4-benzyl-1-piperazinyl)methyl]-N,N-diethylbenzamide, and 4-((4-benzyl-1-piperazinyl){3-[(methylsulfonyl)amino]phenyl}methyl)-N,N-diethylbenzamide.
7. A compound according to any of the preceding claims, in form of its hydrochloride, dihydrochloride, sulfate, tartrate, ditrifluoroacetate or citrate salts.
8. A process for preparing a compound of formula I wherein R4 is -OH, comprising reacting a compound of the general formula II

wherein R2 and R3 are as defined in claim 1 and R4 is OMe, with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Boc protection group under standard conditions to give a compound of the Formula III

which is thereafter alkylated under reductive conditions with a compound of the Formula R1-CHO, followed by cleavage of the methyl ether using BBr3 in dichloromethane to give a compound of the Formula I wherein R4 is -OH.
9. A process for preparing a compound of formula I wherein R4 is -NH2, comprising reacting a compound of the general formula IV

wherein R2 and R3 are as defined in claim 1 and R4 is NO2, with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the Boc protection group under standard conditions to give a compound of the Formula V

which is thereafter alkylated under reductive conditions with a compound of the Formula R1-CHO, followed by reduction of the vitro group using hydrogen and palladium on charcoal to give a compound of the Formula I wherein R4 is NH2.
10. A process for preparing a compound of formula I wherein R4 is -NHSO2R5, comprising reacting a compound of the general formula VI

wherein R2 and R3 are as defined in claim 1 and R4 is NO2, with Boc-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed reduction of the nitro group by hydrogenolysis using palladium on charcoal as the catalyst, metanesulphonylation using methanesulphonylanhydride in dichloromethane in the presence of triethylamine, and thereafter removal of the Boc protection group under standard conditions to give a compound of the Formula VII

which is thereafter alkylated under reductive conditions with a compound of the Formula R1-CHO, followed by reduction of the nitro group using hydrogen and palladium on charcoal to give a compound of the Formula I wherein R4 is -NHSO2R5.
11. A compound according to any of claims 1-7 for use in therapy.
12. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of pain, anxiety of functional gastrointestinal disorders.
13. A pharmaceutical composition comprising a compound of the formula I
according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.
14. A method for the treatment of pain, whereby an effective amount of a compound of the formula I according to claim 1 is administered to a subject in need of pain management.
15. A method for the treatment of functional gastrointestinal disorders, whereby an effective amount of a compound of the formula I according to claim 1, is administered to a subject suffering from said functional gastrointestinal disorder.
CA2446326A 2001-05-18 2002-05-16 4(phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestinal disorders Expired - Fee Related CA2446326C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE0101772-2 2001-05-18
SE0101772A SE0101772D0 (en) 2001-05-18 2001-05-18 Novel compounds
SE0103820A SE0103820D0 (en) 2001-11-15 2001-11-15 Novel compounds
SE0103820-7 2001-11-15
PCT/SE2002/000956 WO2002094794A1 (en) 2001-05-18 2002-05-16 4 (phenyl-piperazinyl-methyl) benzamide derivatives and their use for the treatment of pain anxiety or gastrointestinal disorders

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CA2446326A1 true CA2446326A1 (en) 2002-11-28
CA2446326C CA2446326C (en) 2010-12-07

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